1.
The Effects of Incretins on Energy Homeostasis: Physiology and Implications for the Treatment of Type 2 Diabetes Mellitus and Obesity.
Source
Department of Endocrinology, Diabetes and Metabolism, "Panagia" General Hospital, Nikolaou Plastira 22, 55132 Thessaloniki, Greece. tzotzas@otenet.gr.
Abstract
Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretin physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide(GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.
- PMID:
- 22272906
- [PubMed - as supplied by publisher]
Essay for the 2011 CIHR/CMAJ award: glucagon-like peptides for metabolic and gastrointestinal disorders.
Epac2-dependent mobilization of intracellular Ca2+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in beta-cells of phospholipase C-epsilon knockout mice.
Source
SUNY Upstate Medical University;
Abstract
Not applicable.
Glucagon-like peptide-1 (GLP-1) receptor agonism improves metabolic, biochemical and histopathological indices of nonalcoholic steatohepatitis (NASH) in mice.
Source
1Novartis Institutes for BioMedical Research.
Abstract
These preclinical studies aimed to (1) increase our understanding the dietary induction of NASH, and, (2) further explore the utility and mechanisms of GLP-1 receptor (GLP-1R) agonism in treating NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of NAFLD/NASH in Lep(ob)/Lep(ob) and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiologic features of NASH (e.g., hepatic steatosis and fibrosis). Administration of AC3174, an exenatide analog and GLP-1R agonist, to Lep(ob)/Lep(ob) and B6 mice attenuated hepatic endpointsin both dietary models. Next, we assessed whether AC3174-mediated improvements in HTF diet-induced NASH were solely due to weight loss. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma ALT and triglycerides, whereas a calorie-restricted weight-matched group demonstrated only modest non-significant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1R's in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support clinical evaluation of the utility of GLP-1R agonists for treatment of NASH.
Chronic GLP-1 Receptor Activation by Exendin-4 Induces Expansion of Pancreatic Duct Glands in Rats and Accelerates Formation of Dysplastic Lesions and Chronic Pancreatitis in the KrasG12D Mouse Model.
Source
Larry L. Hillblom Islet Research Center, University of California Los Angeles (UCLA), David Geffen School of Medicine, Los Angeles, California.
Abstract
Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.
Reversible immortalization of Nestin-positive precursor cells from pancreas and differentiation into insulin-secreting cells.
Source
The Clinical Medical Research Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 518020 Shenzhen, PR China.
Abstract
Pancreatic stem cells or progenitor cells posses the ability of directed differentiation into pancreatic β cells. However, these cells usually have limited proliferative capacity and finite lifespan in vitro. In the present study, Nestin-positive progenitor cells (NPPCs) from mouse pancreas that expressed the pancreatic stem cells or progenitor cell marker Nestin were isolated to obtain a sufficient number of differentiated pancreatic β cells. Tet-on system for SV40 large T-antigen expression in NPPCs was used to achieve reversible immortalization. The reversible immortal Nestin-positive progenitor cells (RINPPCs) can undergo at least 80 population doublings without senescence in vitro while maintaining their biological and genetic characteristics. RINPPCs can be efficiently induced to differentiate into insulin-producing cells that contain a combination of glucagon-like peptide-1 (GLP-1) and sodium butyrate. The results of the present study can be used to explore transplantation therapy of type I diabetes mellitus.
Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.
Radiolabeled glucagon-like peptide-1 analogues: a new pancreatic β-cell imaging agent.
Source
aDepartment of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China bDiagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract
Glucagon-like peptide-1 (GLP-1) is a potent antihyperglycemic hormone. It can induce glucose-dependent insulin secretion. GLP-1 has a short half-life of less than 2 min in vivo due to degradation by the dipeptidyl peptidase-IV. GLP-l analogues, such as exendin-4 and exendin-3, have similar biological activity but a longer in-vivo half-life. Pancreatic β-cells and pancreatic islet cell tumors highly express GLP-1 receptors. Hence, radiolabeled GLP-1 analogues play a potential role in imaging and radiation therapy of pancreatic islet cell tumors as well as in the monitoring of pancreatic β-cell transplantation.
GLP-1, the Gut-Brain, and Brain-Periphery Axes.
Source
INSERM (Institut National de la Sante et de la Recherche Medicale), U1048, Institute of Metabolic and Cardiovascular Diseases Rangueil, University of Toulouse III (Paul-Sabatier), (C.C, R.B), and the Faculty of Pharmacy, Toulouse, France.
Abstract
Glucagon-like peptide 1 (GLP-1) is a gut hormone which directly binds to the GLP-1 receptor located at the surface of the pancreatic β-cells to enhance glucose-induced insulin secretion. In addition to its pancreatic effects, GLP-1 can induce metabolic actions by interacting with its receptors expressed on nerve cells in the gut and the brain. GLP-1 can also be considered as a neuropeptide synthesized by neuronal cells in the brain stem that release the peptide directly into the hypothalamus. In this environment, GLP-1 is assumed to control numerous metabolic and cardiovascular functions such as insulin secretion, glucose production and utilization, and arterial blood flow. However, the exact roles of these two locations in the regulation of glucose homeostasis are not well understood. In this review, we highlight the latest experimental data supporting the role of the gut-brain and brain-periphery axes in the control of glucose homeostasis. We also focus our attention on the relevance of β-cell and brain cell targeting by gut GLP-1 for the regulation of glucose homeostasis. In addition to its action on β-cells, we find that understanding the physiological role of GLP-1 will help to develop GLP-1-based therapies to control glycemia in type 2 diabetes by triggering the gut-brain axis or the brain directly. This pleiotropic action of GLP-1 is an important concept that may help to explain the observation that, during their treatment, type 2 diabetic patients can be identified as 'responders' and 'non-responders'.
Incretin therapy - present and future.
Source
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, One Baylor Plaza-BCM620, Houston, Texas 77030, USA.
Abstract
Although newer treatments for type 2 diabetes (T2D) patients have produced continual improvements in outcome, a large and growing population with prediabetes remains under-treated. In the last few years, incretin-based therapies have become an important treatment option for patients with T2D. There are two classes of incretin agents: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon like peptide 1 (GLP-1) receptor agonists. The ultimate goal of agents within both of these classes is to increase GLP-1 signaling, which results in augmented glucose-induced insulin secretion, inhibition of glucagon secretion, and decreased appetite. This should result in improved regulation of glucose homeostasis. GLP-1 receptor agonists enable patients to achieve significant weight loss. In contrast, DPP-4 inhibitors result in a less dramatic increase in GLP-1 levels; therefore, they are weight neutral. Incretin therapies are currently recommended for use early in the treatment algorithm for T2D patients whose disease is not manageable by diet and exercise alone, but the potential for these agents may be farther reaching. Current studies are evaluating the potential benefits of combining incretin therapies with basal insulin to provide continuous glucose control before and after meals. In addition, these agents may be promising for patients with prediabetes since they effectively reduce glycosylated hemoglobin levels and fasting plasma glucose levels, enable weight control, and have the potential to preserve β-cell function. Clearly, all of these properties are desirable for patients with prediabetes.
Physiology of incretins in health and disease.
Source
Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
Abstract
The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gutpeptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.
Beverage consumption, appetite, and energy intake: what did you expect?
Source
Department of Nutrition Science, Purdue University, West Lafayette, IN, and the Department of Medicine, Indiana University, Indianapolis, IN.
Abstract
BACKGROUND:
Beverage consumption is implicated in the overweight/obesity epidemic through the weaker energy compensation response it elicits compared with solid food forms. However, plausible mechanisms are not documented.
OBJECTIVE:
This study assessed the cognitive and sensory contributions of differential postingestive responses to energy- and macronutrient-matched liquid (in beverage form) and solid food forms and identifies physiologic processes that may account for them.
DESIGN:
Fifty-two healthy adults [mean ± SD age: 24.7 ± 5.5 y; BMI (in kg/m(2)): 26.3 ± 6.3] completed this randomized, 4-arm crossover study. Participants consumed oral liquid and solid preloads that they perceived, through cognitive manipulation, to be liquid or solid in their stomach (ie, oral liquid/perceived gastric liquid, oral liquid/perceived gastric solid, oral solid/perceived gastric liquid, or oral solid/perceived gastric solid). However, all preloads were designed to present a liquid gastric challenge. Appetite, gastric-emptying and orocecal transit times, and selected endocrine responses were monitored for the following 4 h; total energy intake was also recorded.
RESULTS:
Oral-liquid and perceived gastric-liquid preloads elicited greater postprandial hunger and lower fullness sensations, more rapid gastric-emptying and orocecal transit times, attenuated insulin and glucagon-like peptide 1 release, and lower ghrelin suppression than did responses after oral-solid and perceived gastric-solid treatments (all P < 0.05). Faster gastric-emptying times were significantly associated with greater energy intake after consumption of perceived gastric-liquid preloads (P < 0.05). Energy intake was greater on days when perceived gastric-liquid preloads were consumed than when perceived gastric solids were consumed (2311 ± 95 compared with 1897 ± 72 kcal, P = 0.007).
CONCLUSIONS:
These data document sensory and cognitive effects of food form on ingestive behavior and identify physical and endocrine variables that may account for the low satiety value of beverages. They are consistent with findings that clear, energy-yielding beverages pose a particular risk for positive energy balance. This study is registered at clinicaltrials.gov as NCT01070199.
The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death.
Source
Department of Endocrinology; The First Affiliated Hospital of Harbin Medical University; Harbin, China.
Abstract
In pancreatic β-cells, the endoplasmic reticulum (ER) is the crucial site for insulin biosynthesis, as this is where the protein-folding machinery for secretory proteins is localized. Perturbations to ER function of the β-cell, such as those caused by high levels of free fatty acid and insulin resistance, can lead to an imbalance in protein homeostasis and ER stress, which has been recognized as an important mechanism for type 2 diabetes. Macroautophagy (hereafter referred to as autophagy) is activated as a novel signaling pathway in response to ER stress. In this review, we outline the mechanism of ER stress-mediated β-cell death and focus on the role of autophagy in ameliorating ER stress. The development of drugs to take advantage of the potential protective effect of autophagy in ER stress, such as glucagon like peptide-1, will be a promising avenue of investigation.
Uncoupling Protein 2 Negatively Regulates Glucose-Induced Glucagon-Like Peptide-1 (GLP-1) Secretion.
Source
H Zhang, Gastroenterology, The First Affiliated Hospital of Nanjing Medical University.
Abstract
Objective: It is known that endogenous levels of the incretin hormone glucagon-like peptide-1 (GLP-1) can be enhanced by various secretagogues, but the mechanism underlying GLP-1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP-1 secretion in mouse intestinal tract and in NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Methods: Localization of UCP2 and GLP-1 in the gastrointestinal tract was assessed by immuno-fluorescence staining. UCP2 mRNA levels in gut were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP-1 (7-36) amide were measured using an ELISA kit. Results: UCP2 was primarily expressed in mucosal layer and co-localized with GLP-1 in gastrointestinal mucosa. L cells secreting GLP-1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP-1 secretion compared with wild-type littermates. GLP-1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly up-regulated in ileum tissue from ob/ob mice, and GLP-1 secretion was decreased compared with normal mice. Furthermore, GLP-1 secretion increased after administration of genipin by oral gavage. Conclusion: Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP-1 secretion.
Antiapoptotic Actions of Exendin-4 against Hypoxia and Cytokines Are Augmented by CREB.
Source
Section of Endocrinology (K.V., S.P.), Veterans Affairs Medical Center, Denver, Colorado 80220; Department of Medicine (K.V., S.P.), University of Colorado Denver, Aurora, Colorado 80045; Schulze Diabetes Institute (A.N.B., G.L., B.J.H.), Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455; and Department of Pediatrics (A.A.), National Jewish Health, Denver, Colorado 80206.
Abstract
Islets isolated from cadaveric donor pancreas are functionally viable and can be transplanted in diabetic patients to reduce insulin requirements. This therapeutic approach is less efficient because a significant portion of functional islets is lost due to oxidative stress, inflammation, and hypoxia. Exendin-4, a glucagon-like peptide-1 receptor agonist, is known to improve islet survival through activation of the transcription factor, cAMP response element binding protein (CREB). However, isolated human islets are exposed to several stresses known to down-regulate CREB. The objective of the present study was to determine whether the cytoprotective actions of exendin-4 in human islets can be augmented by increasing the levels of CREB. Simulation of ischemia/reperfusion injury and exposure to hypoxic conditions in cultured human islets resulted in decreased CREB activation and induction of apoptosis. Islets were transduced with adenoviral CREB followed by exposure to exendin-4 as a strategy for improving their survival. This combination increased the levels of several proteins needed for β-cell survival and function, including insulin receptor substrate-2, Bcl-2, and baculoviral IAP repeat-containing 3, and suppressed the expression of proapoptotic and inflammatory genes. A combination of CREB and exendin-4 exerted enhanced antiapoptotic action in cultured islets against hypoxia and cytokines. More significantly, transplantation of human islets transduced with adenoviral CREB and treated with exendin-4 showed improved glycemic control over a 30-d period in diabetic athymic nude mice. These observations have significant implications in the therapeutic potential of exendin-4 and CREB in the islet transplantation setting as well as in preserving β-cell mass of diabetic patients.
Disruption of the Murine Glp2r Impairs Paneth Cell Function and Increases Susceptibility to Small Bowel Enteritis.
Source
Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute (S.-J.L., J.L., K.K.L., D.H., B.Y., D.J.D.), and the Department of Cell and Systems Biology (H.M., D.S.G.), University of Toronto, Toronto Ontario, Canada M5G 1X5.
Abstract
Exogenous glucagon-like peptide-2 receptor (GLP-2R) activation elicits proliferative and cytoprotective responses in the gastrointestinal mucosa and ameliorates experimental small and large bowel gut injury. Nevertheless, the essential physiological role(s) of the endogenous GLP-2R remain poorly understood. We studied the importance of the GLP-2R for gut growth, epithelial cell lineage allocation, the response to mucosal injury, and host-bacterial interactions in Glp2r(-/-) and littermate control Glp2r(+/+) mice. Glp2r(-/-) mice exhibit normal somatic growth and preserved small and large bowel responses to IGF-I and keratinocyte growth factor. However, Glp2r(-/-) mice failed to up-regulate intestinal epithelial c-fos expression in response to acute GLP-2 administration and do not exhibit changes in small bowel conductance or small or large bowel growth after administration of GLP-2R agonists. The crypt and villus compartment and the numbers and localization of Paneth, enteroendocrine, and goblet cells were comparable in Glp2r(+/+) vs. Glp2r(-/-) mice. Although the severity and extent of colonic mucosal injury in response to 3% oral dextran sulfate was similar across Glp2r genotypes, Glp2r(-/-) mice exhibited significantly increased morbidity and mortality and increased bacterial translocation after induction of enteritis with indomethacin and enhanced mucosal injury in response to irinotecan. Moreover, bacterial colonization of the small bowel was significantly increased, expression of Paneth cell antimicrobial gene products was reduced, and mucosal bactericidal activity was impaired in Glp2r(-/-) mice. Although the Glp2r is dispensable for gut development and the response to colonic injury, Glp2r(-/-) mice exhibit enhanced sensitivity to small bowel injury, and abnormal host-bacterial interactions in the small bowel.
Myocardial Insulin Signaling and Glucose Transport Are Up-regulated in Goto-Kakizaki Type 2 Diabetic Rats After Ileal Transposition.
Source
Department of General Surgery, Qilu Hospital of Shandong University, 107#, Wenhua Xi Road, Jinan, 250012, Shandong, People's Republic of China.
Abstract
BACKGROUND:
Ileal transposition (IT) as one of the effective treatments for non-obese type 2 diabetes mellitus has been widely investigated. However, the mechanisms underlying profound improvements in glucose homeostasis are still uncertain. Our objective was to explore the myocardial insulin signal transduction and glucose disposal in non-obese type 2 diabetes mellitus rats after IT surgery.
METHODS:
Adult male Goto-Kakizaki (GK) rats or Sprague-Dawley (SD) rats were randomly assigned to diabetic IT, diabetic sham-IT, and non-diabetic control SD groups. Food intake, body weight, fasting plasma glucose, insulin tolerance, and serum glucagon-like peptide-1 (GLP-1) were measured. Subsequently, the myocardial glucose uptake and the protein levels of insulin receptor-beta (IR-β), phosphorylated IR-β, insulin receptor substrate 1 (IRS-1), phosphorylated IRS-1, and IRS-1-associated phosphatidylinositol-3 kinase (PI3K) from myocardial cell lysates were evaluated. We also assessed the expression of glucose transporter 4 (GLUT4) in both skeletal muscle and myocardial cell lysates.
RESULTS:
Compared to sham operations within 6 months, IT surgery for GK rats did (1) result in less food intake and reduced body weight gain over time, (2) improve plasma glucose homeostasis with increased serum GLP-1 secretion and myocardial glucose uptake, (3) increase protein expression of insulin signaling pathway, including IR-β, IRS-1 and their phosphorylation levels, and IRS-1-associated PI3K in the myocardium, and (4) enhance the protein levels of membrane GLUT4 in skeletal muscle and myocardium.
CONCLUSIONS:
IT surgery ameliorates glucose disorder in GK type 2 diabetic rats. Meanwhile, IT surgery is effective in up-regulating both myocardial insulin signaling and glucose disposal within 6 months.
Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner.
Source
1] Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China [2] Department of Psychology, School of Art and Science University of Pennsylvania, Philadelphia, PA, USA.
Abstract
Background:The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation.Design and Results:Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery.Conclusions:Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.International Journal of Obesity advance online publication, 17 January 2012; doi:10.1038/ijo.2011.265.
[Glucagon and glucagon-like peptides the role in control glucose homeostasis. Part I].
Abstract
Glucose homeostasis is controlled primarily by the opposing actions of insulin and glucagon, hormones that are secreted by the islets of Langerhans from β-cells and α-cells and Δ-cells, their role in glucose homeostasis still needs identifying. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscles and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Glucagon secretion from pancreatic α-cells is regulated by various mechanisms including glycemia, neural input, and secretion from neighboring β-cells.Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action on the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones.
- PMID:
- 22248782
- [PubMed - in process]
An overview of the pharmacokinetics, efficacy and safety of liraglutide.
Source
Atlanta Diabetes Associates, 77 Collier Rd, Suite 2080, Atlanta, GA 30309, USA.
Abstract
OBJECTIVE:
Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists, are the latest addition to the range of available medications for the management of patients with type 2 diabetes. The GLP-1 analog liraglutide has been approved for use in Europe and the US for over a year and has undergone evaluation in several pharmacokinetic/pharmacodynamics studies and in an extensive phase 3 clinical program. The aim of this review is to assess the pharmacokinetics, efficacy and safety of the phase 3 data.
METHODS:
Data are presented from the pharmacokinetics/pharmacodynamics studies of liraglutide and from nine published phase 3 studies, including the six Liraglutide Effect and Action in Diabetes (LEAD) studies.
RESULTS:
Liraglutide is effective at improving indices of glycemic control, and has a good tolerability and safety profile. Beneficial effects on weight (mean reduction of 1-3.4kg) and blood pressure (systolic blood pressure decreased by 2.1-6.7mmHg) are also observed.
CONCLUSION:
Liraglutide is an effective and well tolerated option for the treatment of type 2 diabetes.
Copyright © 2012. Published by Elsevier Ireland Ltd.
Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures.
Source
Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Republic of Korea; Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Republic of Korea.
Abstract
Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. In this context, anti-diabetic agents such as rosiglitazone and glucagon-like peptide (GLP)-1 have been reported to reduce pathologies associated with AD, including tau hyperphosphorylation, suggesting that such agents might be used to treat AD. One such anti-diabetic agent is sitagliptin, which acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels. Given this action, sitagliptin would be predicted to reduce AD pathology. Accordingly, we investigated whether sitagliptin is effective in attenuating AD pathologies, focusing on tau phosphorylation in the OLETF type 2 diabetic rat model. Unexpectedly, we found that sitagliptin was not effective against pathological tau phosphorylation in the hippocampus of OLETF type 2 diabetes rats, and instead aggravated it. This paradoxically increased tau phosphorylation was attributed to activation of the tau kinase, GSK3β (glycogen synthase kinase 3β). Sitagliptin also increased ser-616 phosphorylation of the insulin receptor substrate (IRS)-1, suggesting increased insulin resistance in the brain. These phenomena were recapitulated in primary rat cortical neurons treated with sitagliptin, further confirming sitagliptin's effects on AD-related pathologies in neurons. These results highlight the need for caution in considering the use of sitagliptin in AD therapy.
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